Background: Many agents have shown survival advantage in metastatic castrate-resistant prostate cancer (mCRPC). Despite this improvement, survival is poor, especially in subgroup of elderly patients who are not fit for cytotoxic chemotherapy. Materials and Methods: This is a single-institutional data review of mCRPC treated between December 2012 and May 2016 with oral cyclophosphamide (50–100 mg/day) ± oral prednisolone. mCRPCs failed or not fit for docetaxel and/or abiraterone were included in this study. Monthly prostate-specific antigen (PSA) was monitored, and toxicity of cyclophosphamide was recorded. PSA response was defined as ≥50% reduction from precyclophosphamide value. The median follow-up was calculated from the day of starting cyclophosphamide and the last date of follow-up or death, whichever is later. Results: Eighteen patients were included with a median age of 74.5 years (range: 59–83). The site of metastasis was bone in 15, bone and distant lymph nodes in 2, and rectum in 1 patient. The median duration of androgen deprivation was 21 months (range: 3–42.9 months). The median cyclophosphamide exposure was 2 months (range: 0.9–13.5 months) after a median follow-up of 5.8 months. Overall PSA response rate was 44%. The median PSA progression-free survival with cyclophosphamide was 4.7 months (range: 0.9–13.5 months). Five patients had durable PSA response of 9.9, 10.1, 10.5, 12.1, and 13.5 months, respectively. No Grade 3 or 4 toxicity was observed with cyclophosphamide. Conclusion: Oral metronomic cyclophosphamide was found to be an effective and well-tolerated therapy in mCRPC after failure or not fit for docetaxel and/or abiraterone. In few patients, cyclophosphamide induced durable PSA response. This finding needs further evaluation in a prospective manner.

Prostate cancer ranks second in world ranking list of all types of cancer among males. The incidence of prostate cancer in India varies according to the region, but it is in the top 10 cancers among males.[1] According to GLOBOCAN 2012, the estimated prostate cancer incidence in India is <10.8/100,000 population.[2] Treatment of localized prostate cancer includes surgery, radiation, or both in combination with androgen deprivation therapy. However, androgen deprivation therapy is the backbone of treatment for metastatic prostate cancer. Recent evidences have shown support for chemohormonal therapy in patients with upfront metastatic prostate cancer who present with advanced disease.[3] For metastatic castrate-resistant prostate cancer (mCRPC), chemotherapy is the treatment of choice. Docetaxel, abiraterone acetate, and enzalutamide are used based on clinical criteria and show marked prolongation in survival. However, all the patients do progress eventually over time and the outcome is poor after failure of these agents. These agents in addition to cabazitaxel can be used sequentially in progressive settings.[4] But during progression, patient's general condition restricts the usage of these drugs with additional burden of finance in resource-poor setting (like India) and with ultimate poor outcome. Transformation from hormone-sensitive prostate cancer to castrate-resistant disease depends on many factors. They are increased angiogenesis, impaired apoptosis, activation of receptor tyrosine kinase activity, and alteration in DNA repairing system in addition to its dependence on androgen.[4] The angiogenic switch plays a crucial role in the development of mCRPC. Reports of efficacy of low-dose cyclophosphamide with or without steroids as metronomic in mCRPC are described in the literature.[5] The basis of using endoxan at low doses is due to its antiangiogenic mechanism. Here, we report our experience with usage of metronomic therapy in advanced prostate cancer.

» Materials and Methods

Patient

This is a retrospective review of patients with mCRPC who were treated between December 2012 and May 2016 with oral cyclophosphamide in our hospital. Patients with mCRPC who had prostate-specific antigen (PSA) progression (defined as two consecutive increase in PSA value) after receiving docetaxel, abiraterone, or both and were not fit for, could not afford for chemotherapy, or refused further chemotherapy were included in this study.

Treatment and response evaluation

Patients were started on oral cyclophosphamide at doses of 50–100 mg/day. Cyclophosphamide dose was increased to 100 mg/day in case of no response with 50 mg/day. In addition, steroids were given to nonresponders. They were followed up every month clinically and with serum PSA till disease progression or unacceptable toxicity. PSA response was assessed by Prostate Specific Antigen Working Group recommendations for outcome guidelines. Toxicity was assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 toxicity criteria.

Statistical analysis

Chi-square test was used to detect association between categorical variables. Student's t-test was applied to compare continuous variables between groups. Survival was estimated by Kaplan–Meier method and compared using log-rank test. Data were censored on August 31, 2016. PSA progression-free survival was calculated from the date of starting cyclophosphamide to the date of PSA progression or date of the last follow-up in those without any progression. Overall survival (OS) was calculated from the date of diagnosis to the date of death from any cause or date of last follow-up in case of alive. Stata/SE version 11.0 (StataCorp LP, College Station, TX, USA) was used for statistical analysis.

» Results

A total of 18 patients were included with a median age of 74.5 years (range: 59–83 years). Baseline characteristics of the patients are shown in [Table 1]. The median duration of androgen deprivation was 21 months (range: 3–42.9 months). The site of metastasis was bone in 15, bone and distant lymph nodes in 2, and rectum in 1 patient. Precyclophosphamide treatment characteristics were docetaxel only in two, abiraterone only in six, sequential treatment with docetaxel and abiraterone in five, and no cytotoxic treatment after mCRPC in five patients. The median PSA in our study group was 38 ng/dL (range: 11–411 ng/dL). The median cyclophosphamide exposure was 2 months (range: 0.9–13.5 months) after a median follow-up of 5.8 months. Overall PSA response rate was 44%: five patients had PSA response and three patients had stable PSA. The median PSA progression-free survival with cyclophosphamide was 4.7 months (range: 0.9–13.5 months) as shown in [Figure 1]. Two patients had durable PSA response of more than a year. No Grade 3 or 4 toxicity was observed with cyclophosphamide.

Table 1: Baseline characteristics and outcome of the patients treated with metronomic therapy

Patients with mCRPC are traditionally treated with systemic chemotherapy in the backdrop of androgen deprivation therapy. Patients do progress on chemotherapy, and there are multiple options to choose from second- and third-line settings with a median OS of 15.1 months.[6] However, factors such as poor performance status, uncontrolled comorbidities, treatment-related toxicity, and high financial costs should be considered while prescribing subsequent therapies in resource-challenged settings. At the same time, maintaining good quality of life (QoL) is an important factor besides survival when choosing treatment in patients with mCRPC. Reports of oral cyclophosphamide and steroids with clinically meaningful efficacy with favorable toxicity profile in patients with mCRPC who were pretreated with chemotherapy with favorable toxicity profile have been described in literature [Table 2].

The median age of our study population was 74.5 years which is comparable to the study by Ladoire et al.[7] PSA response with cyclophosphamide and steroids was for 8 months as shown in a study done by Glode et al.[8] In our study, it was 4.7 months which was similar to that seen in Dickinson et al.[9] PSA response rate by >50% was maximum in a study by Dickinson et al.,[9] which was 69% and in our study it was 27%. Overall PSA response rate was 44% in the study group. We did not observe any Grade 3 or Grade 4 treatment-related toxicities.

Conventionally, chemotherapy is given at maximum tolerated doses at timely interval to destroy the cancer cells and to avoid lethal toxicity. However, they do create adverse side effects. Another mode of administering chemotherapy is giving it repetitively at low doses and it is called as metronomic therapy. The basis for this type of administration is that it targets against the tumor vasculature leading to control of tumor. In addition, immune modulation is another postulated mechanism for tumor control.[10] Metronomic chemotherapeutic administration has lower rates of toxicity due to low doses of agent. Metronomic chemotherapy has been found to produce durable response rates in various solid and hematologic malignancies.[11]

Prostate cancer progression in CRPC setting is due to a number of factors which lead to tumor growth independent of androgen deprivation. One of the most important factors is due to increased angiogenesis secondary to increased vascular endothelial growth factor (VEGF) expression.[12] Cyclophosphamide at low doses targets the dividing endothelial cells, thus inhibiting angiogenesis. Increased production of anti-angiogenic thrombospondin 1 increased its anti-angiogenic action.[13] In addition, it suppresses immune regulatory T cells (Treg cells) which create an immunosuppressive environment to flourish tumor growth. Thus, cyclophosphamide acts as an immune modulator to improve immune surveillance against cancerous cells.[14] Glucocorticoids inhibit androgen production by exerting an inhibitory feedback on the pituitary gland.[15] Due to its inhibitory action against VEGF and interleukin-8 production, steroid has supplementary antiangiogenic and immunomodulatory activities.[16] Because of their synergistic activities, the combination of cyclophosphamide and steroids has shown to be active in mCRPC.

Our study has few limitations. It was a retrospective study, and the study group was too small to derive any conclusion. Dose of cyclophosphamide was not uniform in all patients, and for some dose increment was done in case of poor PSA response. Steroid was not uniformly given among the study population. QoL was not assessed in a systemic manner in our study.

There are many unanswered questions – who are the ideal candidates for oral metronomic therapy? Should it be combined with other drugs such as etoposide or with upfront chemotherapy? Questions regarding the dose and timing of cyclophosphamide have not been answered yet.

It is always not feasible to prove the efficacy of metronomic therapy in prospective randomized controlled trials. Ideally, a properly controlled prospective multicenter study with assessment of QoL is required to make the combination of metronomic cyclophosphamide and steroids a well-proven treatment modality in patients with mCRPC who have progressed on systemic chemotherapy. It would be prudent to include biomarkers such as serum VEGF-I and II with Treg cell activity in this setting to correlate clinical activity with in vivo activity of oral metronomic cyclophosphamide. Future studies can be conducted to see whether addition of oral low-dose cyclophosphamide with chemotherapy or hormonal therapy is useful for disease control in hormone-sensitive prostate cancer too.

» Conclusion

Oral metronomic cyclophosphamide has clinical activity in chemorefractory mCRPC and can be a feasible option in unfit patients and resource-poor setting, even before chemotherapy. Further larger (multicenter) biomarker coupled prospective studies can provide answers for many unanswered research questions.